(Philadelphia, PA) – Very little is known about
how aortic aneurysms initially form and progress. Now,
researchers from the University of Pennsylvania
School of Medicine have shown in an atherosclerotic
animal model that susceptibility for developing aneurysms
increases significantly when an inflammation pathway
important in asthma is activated. Mice without the inflammation
gene were protected from aneurysms.

Colin D. Funk, PhD, former Professor
of Pharmacology and Medicine, and Lei Zhao,
MD, PhD, Research Associate, both in Penn’s
Center for Experimental Therapeutics, report their findings
in this week’s online publication and the September
issue of Nature Medicine. Funk is now the Canada
Research Chair in Molecular, Cellular and Physiological
Medicine, Queen's University, Kingston, Canada.

“This is the first time anyone has ever shown
aneurysm formation associated with this inflammation
pathway,” says Funk. Drugs that block the formation
and action of this pathway are currently used to treat
inflammation in the airways of asthmatics. “Perhaps
they may become useful to treat patients who are susceptible
to developing aortic aneurysms by blocking their progression
and eventual rupture,” he adds.

A gene for the 5-lipoxygenase-activating protein, which
is required to synthesize leukotrienes, potent inflammatory
molecules, has been associated with heart-disease risk.
Leukotrienes, which constrict airways in asthmatics
and contribute to inflammation in the lungs, are also
associated with cardiovascular disease. They are secreted
by inflammatory cells that gather at injured blood vessels.

Abdominal
aortic aneurysms are a bulging region – up to
twice the normal diameter – in the largest artery
of the body. (Click on thumbnail to view full-size image).
There is no known cure, with the only option of “watchful
waiting” until surgical repair is attempted, says
Funk. Often, but not always, these types of aneurysms
are associated with arteriosclerosis, a chronic inflammatory
disease of the blood-vessel wall, consisting of fatty
deposits that progress into major plaques that eventually
break off from the inner lining and lead to heart attacks.
“The danger of aneurysms is that we don’t
normally carry out routine screening for their detection
and by the time they are found most of the progressive
damage may have already occurred,” explains Funk.

“This is a surprising finding since at first we
weren’t even looking for aneurysms, we were trying
to confirm the arteriosclerosis-leukotriene connection,”
comments Zhao. The researchers found the 5-lipoxygenase
enzyme mainly in macrophages in the outer layer of blood
vessels not in the fatty atherosclerotic lesions of
the inner layer, as expected. (Macrophages engulf such
foreign objects as cellular debris, excess fats, and
dying cells.) When the researchers inactivated the gene
in a mouse model of arteriosclerosis, the number and
degree of severity of aneurysms in the mice was markedly
reduced. “In humans it has been very difficult
to characterize the mechanisms for aneurysm formation
and progression,” says Funk. “Often, studies
have only revolved around pathological specimens obtained
at autopsy or at the time of surgery.”

They concluded that leukotrienes derived from 5-lipoxygenase
are one important clue in the progression of aneurysms
but not in early atherosclerosis. More studies will
be required in other models of aneurysm formation and
in larger animals using currently available 5-lipoxygenase
blockers before testing can begin in humans, say the
researchers.

Penn colleagues on the paper are: Daniel J. Rader, Fredérique
Pédrono, and Jinjin Fan. This research was funded
in part by the National Institutes of Health and the
American Heart Association.

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